[Towards better management for sexual offenders: Presentation and conclusions of a public hearing concerning prevention, assessment, and care]. / Audition publique auteurs de violences sexuelles : prévention, évaluation, prise en charge des 14 et 15 juin 2018 : perspectives et préconisations.

In France, since the law of June 17, 1998, sexual offenders may be convicted to ambulatory mandatory care, articulated with the justice. Twenty years after the implementation of this law, while social and technological developments have redefined certain aspects of delinquency, reference documents and practice guidelines remain to be updated. This is why the professionals of the main structures and associations dealing with perpetrators of sexual violence organized a public hearing under the sponsorship of the French Federation of Resource Centers for Sexual Violence Perpetrators (FFCRIAVS) according to the methodology and with the accompaniment of the High Authority of Health. This article presents the global methodology of the public hearing "Sexual Offenders: Prevention, Evaluation and Care" which was conducted on June 14 and 15, 2018. Thirty-three experts replied to27 questions and presented their conclusions to an Audition Committee and an audience of 200 persons representative of the civil and professional society. After a public debate, the hearing committee prepared a report in which they proposed propositions in order to better care for sexual offenders.

Glycaemic and insulinaemic responses of adult healthy warm-blooded mares following feeding with Jerusalem artichoke meal.

This study aimed to investigate the impact of the supplementation of a pre-biotic compound [Jerusalem artichoke meal (JAM)] on the glycaemic and insulinaemic response in healthy, non-obese warm-blooded horses. Six adult mares [mean body weight (bwt) 529 ± 38.7 kg; body condition score 5.1 ± 0.49/9] were used. In two equal meals per day, the horses received crushed oat grains (1 g starch/kg bwt per day) and meadow hay (2 kg/100 kg bwt per day) which together were likely to meet the energy recommendation for light work (GfE, ). Additionally, they received either 0.15 g fructo-oligosaccharides and inulin (FOS+INU)/kg bwt per day via commercial JAM or maize cob meal without grains as control (CON) in 2 × 3-week periods according to a crossover design. Blood was collected on d21 of the feeding period at different ante- and postprandial (PP) time points (-60, 0, 30, 60, 90, 120, 180, 240 and 300 min), and the plasma glucose and serum insulin levels were determined. Feeding JAM vs. CON did not change the PP peak of glucose or insulin (glucose: 6.3 ± 0.40 vs. 7.0 ± 0.87 mmol/l; insulin: 0.508 ± 0.087 vs. 0.476 ± 0.082 nmol/l) nor did it cause different AUCs until 120 and 300 min PP for glucose and insulin, respectively (AUC120 , glucose: 997 ± 41.6 vs. 1015 ± 41.63 mmol/l per minute, insulin: 49 ± 6.3 vs. 42 ± 6.3 nmol/l per minute; AUC300 , glucose: 1943 ± 142.3 vs. 2115 ± 142.3 mmol/l per minute, insulin: 94 ± 14.8 vs. 106 ± 14.8 nmol/l per minute; p > 0.05). Following JAM vs. CON feeding, glucose and insulin levels declined more rapidly until 240 min PP and tended to be lower (p = 0.053 and p = 0.056, respectively) at this time point. This result might be promising and should further be studied more detailed.

A temporary filling material used for coronal sealing during endodontic treatment may cause tooth fractures in large Class II cavities in vitro.

AIM: To investigate the use of a zinc oxide/zinc sulphate-based cement (Coltosol(®) F, Coltène Whaledent, Cuyahoga Falls, OH, USA) as a temporary filling material during multiple-visit root canal treatments and the occurrence of cracks within the filling material or the tooth. METHODOLOGY: Root canals of one hundred and twenty-two extracted human molars were prepared using ProTaper instruments up to size F2. After root canal preparation, standardized mesial-occlusal-distal cavities were prepared. The buccal-lingual/palatal width of the cavities was 4.5 mm), so that the remaining cavity walls had a mean thickness of 3.5 mm. Teeth were checked for cracks and fracture lines using a stereomicroscope with 10× magnification. A calcium hydroxide slurry was used as an intracanal dressing. The teeth were divided into three groups. In the Coltosol group, the cavity was filled with Coltosol(®) F. In the Coltosol-Clearfil group, a 2-mm layer of Coltosol(®) F was placed into the coronal pulp chamber, the remaining cavity was filled with Clearfil(™) . In the Clearfil group, a foam pellet was placed onto the orifices of the root canals, the remaining cavity was filled with Clearfil(™) . In the control group, the cavities were left without any filling material. The teeth were stored in water at 37 °C for 14 days and examined every 24 h under a stereomicroscope for fracture lines occurring on the tooth surface or in the filling material. RESULTS: In the Coltosol group, fractures within the filling material were observed in 28 (85%) of 33 teeth. 13 (39%) teeth had tooth fractures. Amongst these teeth, 8 (61%) had root fractures, 1 (8%) had a crown fracture and 4 (31%) had a root-crown fracture. CONCLUSION: Coltosol(®) F, when used alone as a restorative material, led to tooth fractures in Class II cavities in teeth undergoing root canal treatment. Tooth fractures may occur 4 days after placement of the filling.

The intubation scoop (i-scoop) - a new type of laryngoscope for difficult and normal airways.

The i-scoop is an intubation device with a curved guiding bar with laterally located lenses at its tip, rather than a blade. Twenty-five anaesthesiologists intubated a manikin that simulated first a normal and then a difficult airway. All participants were able to intubate the difficult airway with a good view of the glottis using the i-scoop. None was able to intubate using seven other laryngoscopes (Macintosh laryngoscope, GlideScope(®) GVL and AVL, McGrath(®) (Series 5/MAC), C-MAC(®) , A.P. Advance(™) ). Intubation was successful only with the Airtraq(®) (n = 10), the Airway Scope (n = 5), the C-MAC D-Blade (n = 2), the A.P. Advance DAB (n = 1) and the GlideScope DL Trainer (n = 1) (p < 0.001, success rate of i-scoop vs all 12 laryngoscopes combined). In contrast to all other videolaryngoscopes, intubation of the normal airway with the i-scoop was achieved even faster than with the Macintosh laryngoscope (p < 0.02). The i-scoop outperformed all other laryngoscopes in both difficult and normal airways, and therefore has potential as an easier and safer alternative to present devices.

Influence of human saliva on the development of artificial erosions.

It was hypothesized that saliva from patients with erosion exhibits lower protective efficacy compared to saliva from patients without erosion, based on in vitro enamel softening studies. A total of 645 enamel specimens were distributed among seven experimental groups. Saliva was gathered from each of 10 volunteers without clinical signs of dental erosion and from 10 patients exhibiting severe erosive defects. Aliquots of 50 ml of saliva from each patient were mixed with sour drops or citric acid, respectively. Pooled saliva, sour drops and citric acid mixed with water served as controls. The enamel specimens were soaked in the respective mixture for 5 min and were subsequently incubated in pure saliva for 2 min. This cycle was repeated three times, then the specimens were kept in 100 ml of saliva for 8 h. Surface microhardness was evaluated at the beginning of the experiment and after each cycle. During the experiments, microhardness decreased significantly in all groups except for the pure saliva group. For sour drops and citric acid mixed with saliva from patients without erosion, the final microhardness was higher compared to the mixture of the two erosive compounds with saliva from patients with erosion. The storage of saliva for 8 h resulted in a certain amount of rehardening, with the highest level of rehardening being observed in the group that was least demineralized (sour drops plus saliva from patients without erosion). It is concluded that salivary components play a crucial role in the development of dental erosion.

Comparative susceptibility among three stocks of yellow perch, Perca flavescens (Mitchill), to viral haemorrhagic septicaemia virus strain IVb from the Great Lakes.

The Great Lakes strain of viral haemorrhagic septicaemia virus IVb (VHSV-IVb) is capable of infecting a wide number of naive species and has been associated with large fish kills in the Midwestern United States since its discovery in 2005. The yellow perch, Perca flavescens (Mitchill), a freshwater species commonly found throughout inland waters of the United States and prized for its high value in sport and commercial fisheries, is a species documented in several fish kills affiliated with VHS. In the present study, differences in survival after infection with VHSV IVb were observed among juvenile fish from three yellow perch broodstocks that were originally derived from distinct wild populations, suggesting innate differences in susceptibility due to genetic variance. While all three stocks were susceptible upon waterborne exposure to VHS virus infection, fish derived from the Midwest (Lake Winnebago, WI) showed significantly lower cumulative % survival compared with two perch stocks derived from the East Coast (Perquimans River, NC and Choptank River, MD) of the United States. However, despite differences in apparent susceptibility, clinical signs did not vary between stocks and included moderate-to-severe haemorrhages at the pelvic and pectoral fin bases and exophthalmia. After the 28-day challenge was complete, VHS virus was analysed in subsets of whole fish that had either survived or succumbed to the infection using both plaque assay and quantitative PCR methodologies. A direct correlation was identified between the two methods, suggesting the potential for both methods to be used to detect virus in a research setting.

Diversity of movements by individual anadromous coastal cutthroat trout Oncorhynchus clarkii clarkii.

Wild, downstream-migrating cutthroat trout, Oncorhynchus clarkii clarkii, smolts and adults were captured at a weir in Big Beef Creek, Hood Canal, Washington, surgically implanted with acoustic tags and tracked to identify spring and summer movements using stationary receivers in order to test the assumption that the species moves little while in marine waters. Overall, 93-96% migrated from the stream into the east side of the long narrow fjord, where they dispersed north and south along the shoreline. Most O. c. clarkii were detected nearshore within 10 km of the release site, with declining detection rates to 77 km. Over one-third (36%) crossed c. 2-4 km of deep water to the other side but only one O. c. clarkii left the Hood Canal basin. Movements and behaviour patterns did not differ between smolts and adults but cluster analysis revealed two modes of distribution, here categorized as residents and migrants. Within these categories of overall distribution, a range of finer-scale behaviour patterns was observed, including sedentary individuals, daily moving between proximate sites and more continuous long-distance travel. Diel movement patterns varied markedly among individuals but overall activity increased near dawn, peaked around mid-day and declined but continued at night. These patterns contrast with sympatric and closely related steelhead trout, Oncorhynchus mykiss, providing new insights into the diversity of salmonid behaviour.

EGFR-specific T cell frequencies correlate with EGFR expression in head and neck squamous cell carcinoma.

BACKGROUND: In head and neck squamous cell carcinoma (HNSCC), expression levels of the epidermal growth factor receptor (EGFR) correlate with poor prognosis and decreased survival rates. As the mechanisms responsible for cellular immune response to EGFR in vivo remain unclear, the frequency and function of EGFR-specific cytotoxic T cells (CTL) was determined in HNSCC patients. METHODS: The frequency of CTL specific for the HLA-A2.1-restricted EGFR-derived YLN peptide (YLNTVQPTCV) and KLF peptide (KLFGTSGQKT) was determined in 16 HLA-A2.1+ HNSCC patients and 16 healthy HLA-A2.1+ individuals (NC) by multicolor flow cytometry. Patients' results were correlated to EGFR expression obtained by immunohistochemistry in corresponding tumor sections. Proliferation and anti-tumor activity of peptide-specific CTL was demonstrated by in vitro stimulation with dendritic cells pulsed with the peptides. RESULTS: Frequency of EGFR-specific CTL correlated significantly with EGFR expression in tumor sections (p = 0.02, r2 = 0.6). Patients with elevated EGFR scores (> 7) had a significantly higher frequency of EGFR-specific CTL than NC and patients with low EGFR scores (< 7). EGFR-specific CTL from cancer patients were expanded ex vivo and produced IFN-γ upon recognition of EGFR+ target cells. CONCLUSION: EGFR expressed on HNSCC cells induces a specific immune response in vivo. Strategies for expansion of EGFR-specific CTL may be important for future immunotherapy of HNSCC patients.

Immunological stimuli change expression of genes and neutrophil function in fathead minnow Pimephales promelas Rafinesque.

Fathead minnows Pimephales promelas were exposed to lipopolysaccharide (LPS) and polyinosinic-polycytidylic acid [poly(I:C)] to observe immunological responses during simulated bacterial and viral challenge at the level of gene expression and granulocyte function. Complementary DNA libraries were created from LPS- and poly(I:C)-treated fish and c. 5000 expressed sequence tags (ESTs) were sequenced. The ESTs were subjected to BLASTx analysis and 1500 genes were annotated, grouped by function and 20 immune genes were selected for expression studies by real-time PCR. Lipopolysaccharide treatment significantly downregulated expression of interferon regulatory factor 2 binding protein 1 (nine-fold), Chemokine (C-X-C motif) ligand 12a (three-fold) and TNF-related apoptosis-inducing ligand, TRAIL (two-fold). In poly(I:C)-treated fish, a significant upregulation was observed for IFN-inducible and antiviral proteins belonging to the family of Mx proteins (73-fold) and chemokine CCL-C5a (28-fold). Blood neutrophil count was significantly increased in poly(I:C)-treated fish at 24 and 48 h post-injection. Neutrophil extracellular trap release and respiratory burst of kidney granulocytes were suppressed in poly(I:C)-treated fish, while degranulation of primary granules was not affected significantly by the treatment. The changes in gene expression and neutrophil function in P. promelas exposed to LPS and poly(I:C) support the use of this species as an alternative model for studies of pathogen effects on the innate immune system of fishes.

Developing consumer-directed care for people with a disability: 10 lessons for user participation in health and community care policy and program development.

This paper outlines 10 lessons derived from the development of a consumer-directed care program for families with disabled children in Melbourne, Australia. The following program elements proved to be of importance over the course of the development process: (1) research participants should be involved as early as possible; (2) an open, inclusive communication style in conjunction with a good understanding of potential concerns and a careful framing of the policy issue is required to build trust and allow meaningful collaboration; (3) various strands of evidence have to be woven together; (4) ongoing commitment and support from management and key stakeholders; (5) effective knowledge transfer and cultural change processes; (6) capacity building; (7) mediation of power differentials; (8) community building; (9) participant re-engagement strategies; and (10) solid project management skills.

Overall and relapse-free survival in oropharyngeal and hypopharyngeal squamous cell carcinoma are associated with genotypes of T393C polymorphism of the GNAS1 gene.

PURPOSE: In previous studies, we have shown that the T allele of a specific single-nucleotide polymorphism (SNP) in the Galphas gene (T393C) correlates with increased Galphas expression and hence apoptosis. The T allele was associated with a favorable outcome in a variety of human cancers, e.g., carcinoma of the urinary bladder, kidney, and colorectum. EXPERIMENTAL DESIGN: The prognostic value of the T393C SNP was evaluated in an unselected series of patients treated with curative intent for oropharyngeal and hypopharyngeal squamous cell carcinomas, including all tumor stages with different therapeutic regimens. Genotype analysis was done using DNA from paraffin-embedded tissue samples from 202 patients (162 men, 40 women) with a median follow-up of 38 months (1-133 months). The various genotypes were correlated with relapse-free and overall survival. RESULTS: GNAS1 393C homozygous patients displayed a higher risk for disease progression than T393 homozygous patients (hazard ratio CC versus TT, 1.9; 95% confidence interval, 1.1-3.2; P = 0.019). The same genotype effect was observed for overall survival with CC genotypes at higher risk for death compared with TT genotypes (hazard ratio, 1.7; 95% confidence interval, 1.1-2.9; P = 0.015). Multivariate analysis showed that, besides American Joint Committee on Cancer stage, tumor localization, and gender, the T393C polymorphism was an independent prognostic factor for disease progression and death. CONCLUSION: The T393C SNP could be considered as a genetic marker to predict the clinical course of patients suffering from oropharyngeal and hypopharyngeal cancer.

Association study of the G-protein beta3 subunit C825T polymorphism with disease progression an overall survival in patients with head and neck squamous cell carcinoma.

The T-allele of a common C825T single nucleotide polymorphism (SNP) in the gene GNB3, encoding the G3 subunit of heterotrimeric G-proteins, is associated with a truncated form of the G3 protein that imparts a greater signaling capacity than the alternative C-allele encoding a nontruncated protein. We analyzed the C825T-allele status with regard to disease progression in patients with head and neck squamous cell carcinoma (HNSCC). The prognostic value of the SNP was evaluated in an unselected series of 341 patients treated with curative intent for HNSCC including all tumor stages with different therapeutic regimens. Genotype analysis was done by Pyrosequencing using DNA from paraffin-embedded tissue samples. Genotypes were correlated with relapse-free and overall survival. Proportions of 5-year relapse-free intervals were 62% for CC, 60% for TC, and 42% for TT genotypes. Kaplan-Meier curves revealed a significant genotype-dependent relapse-free interval (P = 0.036). In multivariate analysis with stage, localization, grade, gender, and smoking habits as covariates, GNB3 825T homozygous patients displayed a higher risk for relapse than C825 homozygous patients (TT versus CC, hazard ratio; 95% confidence interval, 1.4-4.8; P = 0.002). The same genotype effect was found for overall survival, TT genotypes were at higher risk for death compared with CC genotypes (hazard ratio, 2.6; 95% confidence interval, 1.6-4.3; P < 0.001), and 5-year survival proportions were 60% for CC, 52% for TC, and 33% for TT. The GNB3 C825T SNP thus represents a host derived prognostic marker in HNSCC, which allows identifying high-risk patients, which could benefit from novel and/or more aggressive therapeutic regimes.

Structural-functional relationships in diabetic nephropathy.

Renal biopsies in 45 patients with insulin-dependent diabetes mellitus (IDDM) were examined by semiquantitative light microscopy and quantitative electron microscopic stereologic morphometry. In these 14 males and 31 females, aged 13-52 yr, who had had IDDM for 2.5-29 yr there was no strong relationship between either glomerular basement membrane (GBM) thickness or mesangial expansion and duration of IDDM. There was only a weak relationship between the thickness of the GBM and expansion of the mesangium. Thus, GBM thickening and mesangial expansion in IDDM occur at rates that often differ from one another and that vary greatly among patients. The clinical manifestations of diabetic nephropathy, albuminuria, hypertension, and decreased glomerular filtration rate related poorly or not at all to GBM thickening. In contrast, all light and electron microscopic measures of mesangial expansion were strongly related to the clinical manifestations of diabetic nephropathy, although in the absence of these clinical findings, it was not possible to predict the severity of any of the diabetic glomerular lesions. Mesangial expansion had strong inverse correlations with capillary filtering surface area density. It is hypothesized that mesangial expansion could lead to glomerular functional deterioration in IDDM by restricting the glomerular capillary vasculature and its filtering surface. However, capillary closure, glomerular sclerosis, and interstitial fibrosis could also contribute to the clinical manifestations of this disorder.

Transcriptional analysis of LPS-stimulated activation of trout (Oncorhynchus mykiss) monocyte/macrophage cells in primary culture treated with cortisol.

Primary immune responses to pathogen invasion are mediated by the innate immune system in which tissue macrophages play a key role. During infectious processes glucocorticoids generally may function to dampen inflammatory responses. In this study, the ability of cortisol to directly modulate the transcriptional response of rainbow trout macrophages to the cellular activator lipopolysaccharide (LPS) was investigated. The results indicate that cortisol significantly inhibits the well-described LPS-dependent induction of the expression of TNF-alpha2, a pro-inflammatory cytokine. In order to further characterize the molecular effects of LPS and the immunomodulatory role of cortisol, the in vitro macrophage response to LPS in the absence or presence of 12-h cortisol exposure was analyzed utilizing a salmonid-specific microarray platform. Genes that were stimulated or inhibited with LPS plus cortisol fell into several major functional groups. The first, a general "response" group comprising genes within ontology classes including the response to external stimuli, stress, humoral immunity and apoptosis, exhibited a significant increase after LPS stimulation, whereas suppression of this response was observed in the presence of cortisol. LPS stimulated other genes in a second group involved in cell signalling and also genes in a third group involved in the activation of transcription. Categories activated with cortisol were mainly related to various aspects of metabolism (including protein biosynthesis, binding and transport of ions) and structural proteins (mainly cytoskeleton and microtubules). The immunomodulatory action of cortisol on LPS-stimulated macrophages therefore appears more complex than simply the antagonism of LPS-induced transcriptional responses.

The SV40 small t-antigen prevents mammary gland differentiation and induces breast cancer formation in transgenic mice; truncated large T-antigen molecules harboring the intact p53 and pRb binding region do not have this effect.

We report here for the first time, that the SV40 small t-antigen inhibits mammary gland differentiation during mid-pregnancy and that about 10% of multiparous WAP-SVt transgenic animals develop breast tumors with latencies ranging from 10-17 months. Cyclin D1 is deregulated and over expressed in the small t-antigen positive mammary gland epithelial cells (ME-cells) and in the breast tumor cells. SV40 small t-antigen immortalized ME-cells (t-ME-cells) exhibit a strong intranuclear cyclin D1 staining, also in the absence of external growth factors and the cells continue to divide for several days without serum. In addition, the expression rate of cyclin E and p21(Waf1) but not of p53 is increased. Coimmunoprecipitation experiments revealed that p21(Waf1) is mainly associated with the cyclin D/CDK4 but not with the cyclin E/CDK2 complex. WAP-SVT transgenic animals exhibit an almost regular mammary gland development until late pregnancy but the majority of the ME-cells are eliminated by apoptosis during the early lactation period. Tumor formation is delayed and less efficient than in T/t-antigen positive animals. Sequestration of p53 and pRb by the N-terminal truncated T-antigen molecules (T1-antigen and T2-antigen) does not affect mammary gland differentiation and the transgenic animals (WAP-SVBst-Bam) do not develop breast tumors.

Evaluating the benefits of human islet transplantation.

For important ethical and practical reasons, present human trials of islet transplantation in diabetes are restricted to subjects already committed to immunosuppression by the need for kidney transplantation. Following the morphology of the transplanted kidney for possible reversal of diabetes-related changes may be the most valuable technique for demonstrating benefit from the restoration of islet function. Amelioration of diabetic vascular disease is the compelling reason for efforts to achieve effective islet transplantation.

Metabolic effect of hemipancreatectomy in donors. Preoperative prediction of postoperative oral glucose tolerance.

Between November 1977 and January 1987, 55 transplantations of pancreas segments from living donors related to their recipients were performed at the University of Minnesota. A preliminary analysis of metabolic test results in donors tested 1 yr after hemipancreatectomy showed an increase in mean glucose and a decrease in mean insulin values during oral glucose tolerance tests (OGTTs) in 18 donors, a 14% increase in the mean of the mean glucose levels during 24-h metabolic profiles in 12 donors, and a decrease of 45% in the mean 24-h urinary C-peptide excretion in 21 donors. Including the studies performed postdonation, 11 of 31 (35%) donors developed an abnormal OGTT result. In a retrospective analysis, preoperative results of intravenous glucose tolerance tests (IVGTTs) and cortisone-stimulated OGTTs were found to be statistically significant predictors of an abnormal OGTT after hemipancreatectomy. The mean of the 5- to 50-min IVGTT insulin values was the best predictive test. With the cutoff value set at 62 microU/ml, this test result had a sensitivity of 100%, a specificity of 83%, and a positive predictive value of 75% for identifying donors who developed an abnormal OGTT. The sum of the 5- and 10-min IVGTT insulin (cutoff 140 microU/ml) had a sensitivity of 100%, a specificity of 67%, and a predictive value of only 60%, whereas the delta-insulin had values of 86, 71, and 60%, respectively. Both the IVGTT mean insulin and the sum of the 5-min and 10-min insulin test results were 100% predictive of an abnormal test (0% risk), but the IVGTT mean insulin excluded the lowest proportion of otherwise suitable donors (a low "false-alarm" rate). The IVGTT mean insulin can be used to identify or exclude potential donors who would develop an abnormal OGTT result should hemipancreatectomy be performed.

Recurrence of disease in pancreas transplants.

In a series of 200 pancreas transplants with 6 mo to less than 9 yr of follow-up, recurrence of disease was identified as the cause of graft failure in 8 cases, all in non- or minimally immunosuppressed recipients of transplants from identical twin (n = 3) or HLA-identical sibling (n = 5) donors. Recurrence of disease was defined as selective loss of beta-cells; other endocrine cell types persisted and appeared normal within the islets of the graft. Isletitis was present in islets with residual beta-cells during the evolution of the process in all nonimmunosuppressed and in some immunosuppressed recipients, but isletitis resolved in all cases in which beta-cell destruction was complete and also resolved in some cases in which residual beta-cells were retained after the introduction of or an increase in immunosuppression. Recurrence of disease can be prevented by immunosuppression, and 2 recipients of identical twin grafts and 12 recipients of grafts from HLA-identical siblings had functioning grafts as of March 1988, the longest greater than 7 yr. The process has not been observed in patients in whom full-dose immunosuppression has been used, including HLA-identical siblings, and this may be the reason no cases of recurrence of disease have been identified in recipients of cadaveric grafts. Alternatively, the observations are consistent with, but not proof of, the hypothesis that recurrence of disease (autoimmune isletitis leading to diabetes) is a major histocompatibility complex-restricted phenomenon.